Hussein A. Tawbi, MD: The COLUMBUS trial was a study that had a phase III component that randomized patients to encorafenib and binimetinib versus single-agent encorafenib versus single-agent vemurafenib. And obviously in that phase III trial, the single-agent vemurafenib was kind of the standard-of-care arm that the combination was expected to be compared with. And so in that study, the encorafenib and binimetinib combination ended up being, showed a better efficacy profile, and the progression-free survival rate was about 14.9 months. The progression-free survival, I should say, not the survival rate, was 14.9 months as compared with 7.2 months for the vemurafenib. And that’s really important, because that was the primary endpoint of the study, the progression-free survival.
The other piece that we feel is very important to kind of help us understand the results of that trial, is actually the standard-of-care vemurafenib arm, because that is the one that was, again, studied in other trials—like when vemurafenib and cobimetinib were compared with vemurafenib alone and dabrafenib and trametinib were also compared with vemurafenib alone. So it’s kind of a way to anchor the results of multiple trials. That arm seemed to actually do just as well as the other vemurafenib arms in the other studies. And so it kind of gives us an inclination to believe that that trial population was about similar to the other trials that studied BRAF and MEK inhibitors.
And so, again, for the results of the immediate trial it was clear that encorafenib and binimetinib were more efficacious than vemurafenib alone in terms of improving PFS [progression-free survival] and actually later on in terms of improving overall survival as well.
Ryan J. Sullivan, MD: The COLUMBUS trial is a clinical trial that actually had a number of different arms, including encorafenib-binimetinib at 450 mg of encorafenib a day and 45 mg twice a day of binimetinib. There’s another arm of 300 mg of encorafenib and 45 mg twice a day of binimetinib. And then there were 2 single-agent BRAF-inhibitor arms plus placebo—1 was encorafenib, and 1 was vemurafenib.
The overall survival data that was presented, and subsequently published in 2018, was focused on looking at the 450 mg encorafenib-containing combo arm against the single-agent vemurafenib-containing arm.
The overall survival for the encorafenib 450 mg binimetinib arm combo was pretty remarkable, with over 3 years of median follow-up. The median overall survival was just over 33 months, which was longer than any other BRAF/MEK inhibitor combination study to date, compared with a median overall survival of, you know, these 17 months for single-agent vemurafenib.
The hazard ratio was 0.61. When comparing across other BRAF/MEK combination arms, it’s a little bit challenging to look at overall survival because the COLUMBUS trial was launched later than the COMBI-d and COMBI-v studies, which were the dabrafenib-trametinib versus dabrafenib, and dabrafenib-trametinib versus vemurafenib studies, respectively. And it was launched after the coBRIM study, which was vemurafenib-cobimetinib versus cobimentinib. However, each of the combinations has been tested in a randomized phase III trial, with the combination being compared with vemurafenib single-agent. So there is some fairness in comparing across trials to see the difference in efficacy and make some statement about whether 1 therapy is better than the other.
In terms of response rate, it doesn’t appear that there’s a major difference when you compare the response rates of all 3 of the combination arms against vemurafenib. When you look at progression-free survival, there isn’t a dramatic difference of any of those 3 combination arms compared with vemurafenib. The number is a little bit better with encorafenib and binimetinib, but it’s not dramatically better. The overall survival number does appear to be better in the hazard ratio. So in the COMBI-d and COMBI-v studies, overall survival was about 2 years, median overall survival was about 2 years, and the hazard ratio for overall survival was in the 0.67-0.7 range.
There are similar data with the coBRIM study and vemurafenib-cobimetinib; whereas in the overall survival data with encorafenib-binimetinib, median survival, 33-plus months, and hazard ratio 0.61. So it does appear that it could be slightly better, although statistically it’s really hard to make that call. And I think the fairest way to say it is, there are some data that suggest that the combination of encorafenib-binimetinib could be better, but it’s not definitive. And so from an efficacy standpoint, it’s probably fair to say all 3 are similar. But there is that ability to compare because of the combination arms, and there does seem to be some—mostly with overall survival, as opposed to progression-free survival of response rate—favoring of the last drug combination to get to the market.
Hussein A. Tawbi, MD: It was really interesting to see that the encorafenib arm actually ended up being more effective than single-agent vemurafenib, which is something I would not necessarily have expected. And it again highlights the fact that that longer kind of duration of inhibition of the BRAF pathway and the fact that there’s a much lower disassociation of encorafenib from its target may actually carry some additional efficacy over vemurafenib alone.
Transcript Edited for Clarity.